1. FIELD OF THE INVENTION
This invention relates to bioresorbable cement setting reagents particularly to those formed from calcium phosphates, and useful in dental and bone cements, bone graft materials, bone substitutes, bone fillers, as a drug release carrier, and in other medical applications.
2. DESCRIPTION OF THE PRIOR ART
The major inorganic constituent of hard tissue is biological apatite. For example, bone has 65% to near 70% of biological apatite, and teeth contain more than 98% biological apatite. Hydroxyapatite is a calcium phosphate compound which has same crystal structure as biological apatite. In principle, hydroxyapatite should be an ideal candidate as hard tissue replacement material. However, the precipitated hydroxyapatite has very fine particle size. Because of manipulation requirements, this hinders the applications of precipitated hydroxyapatite in the medical area. In the last twenty years or so, many types of calcium phosphate ceramics have been prepared. Among these, hydroxyapatite and 62 -tricalcium phosphate ceramics and calcium phosphate containing glass have been extensively studied. Clinical studies confirmed that most of the calcium phosphate ceramics such as hydroxyapatite, tricalcium phosphate, tetracalcium phosphate and dicalcium phosphate have excellent biocompatibility and can be well accepted by both hard tissue and soft tissue. The experimental results also indicated that dense hydroxyapatite is non-bioresorbable while other porous calcium phosphate ceramics are bioresorbable.
Calcium phosphate ceramics have been approved as useful and biocompatible materials for bone substitutes. These include dicalcium phosphate, tricalcium phosphate, apatite compounds and tetracalcium phosphate. Most of the calcium phosphate ceramics for medical application are prepared either as granule form or block form. The granule form has a mobility problem while the block form is very brittle and is difficult to shape. In order to solve the above problems, many attempts have been made to prepare bioresorbable grouts or cementing materials. Among these are Plaster of Paris, collagen and several types of calcium phosphate cement.
Ideally, a useful cementing material for hard tissue application should have good biocompatibility, suitable bioresorption rate, and good setting character with reasonable setting time. Most of the above materials have certain disadvantages. Plaster of Paris have reasonable setting character but the resorption rate is too fast. Collagen-hydroxyapatite composite and polylactate-HA composite can serve as useful delivery system for hydroxyapatite granule. However, these materials can only be made as premolded shape and cannot be molded at the surgical site. Polyacrylic acid calcium phosphate cement is not bioresorbable and the setting cement is too acidic.
Recently, a calcium phosphate cement with bi-functional organic acids or amino acids has been reported (U.S. Pat. No. 4,668,295). However, this cement is also very acidic and disintegrates very fast in the liquid environment. It has been noted that in practice such a cement gives a low pH product which can be irritating and not well tolerated. No ingredients that would raise the pH closer to neutral are disclosed therein.
Pure hydroxyapatite cement prepared by reacting tetracalcium phosphate and other calcium phosphate is not resorbable and does not have good setting character (U.S. Pat. Nos. 4,518,430 and 4,612,053). An octacalcium phosphate cement prepared by reacting hydroxyapatite and dicalcium phosphate has also been reported Oonishi.sup.1 studied the .alpha.-tricalcium phosphate bioactive cement using citric acid as setting reagent. The cement has reasonable setting time and strong mechanical strength However, the cement is very acidic in nature. More, recently a calcium phosphate containing bioglass cement using phosphoric acid or calcium hydroxide as setting reagent has been reported by E. A. Monroe.sup.2 and his co-workers. FNT .sup.1 "Studies on Development of .alpha.-TCP Bioactive Bone Cement" H. Oonishi, et al, Osaka-Minami National Hospital. FNT .sup.2 Abstract Phosphate Glass Bone Graft. Published at the 15th Annual Meeting of the Society for Biomaterials April 28, May 2, 1989 Lake Buena Vista, Fla., U.S.A.
The development of moldable bioresorbable calcium phosphate cement would expand the medical application of calcium phosphate ceramics considerably.
Most of the previous calcium phosphate cements developed used hydroxyapatite and tricalcium phosphate as cementing powder, and used acids such as phosphoric acid, bi-functional organic acids, citric acid or polyacrylic acid. These cements are normally very acidic in nature and take a very long time for them to reach neutral pH. After implantation, these cements would cause irritation and inflammatory reaction. Beside, these cements are difficult to control the setting time and do not have good manipulation characteristics.